Process for producing 5-(3-cyanophenyl)-3-formylbenzoic acid compound

ABSTRACT

A 5-(3-cyanophenyl)-3-formylbenzoic acid compound of the formula (IV) is prepared by reacting a 5-bromo-3-(hydroxymethyl)benzoic acid compound of the formula (I) with manganese dioxide to provide a 5-bromo-3-formylbenzoic acid compound of the formula (II), and then reacting the resultant compound of the formula (II) with 3-cyanophenylboronic acid of the formula (III) in the presence of a palladium complex.  
                 
 
R is a H atom or a C 1 -C 10  alkyl group.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a process for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound. More particularly, thepresent invention relates to a process for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound by procedures, which canbe easily carried out in industrial practice, with high yields and withlow costs.

A 5-(3-cyanophenyl)-3-formylbenzoic acid compound is useful as anintermediate of a clinically applicable inhibitor against selective,activated blood coagulation factor X (which will be referred to asFX_(a) hereinafter).

BACKGROUND ART

Currently, as thrombosis inhibitors, antithrombin agents are employed.The antithrombin agents exhibit, together with the anticoagulationactivity for blood, an inhibiting activity against theplatelet-coagulation effect of thrombin. Therefore, it is known that theantithrombin agents may exhibit a tendency to promote bleeding, and thusthe control of the inhibiting effect the conventional thrombin agentsagainst the blood coagulation is not easy.

In view of the above-mentioned prior art, it is now attempted to developa new blood coagulation-inhibiting agent on a basis of an activationmechanism different from that of the blood coagulation-inhibitingactivity of the conventional thrombin agents. For example, WO 99/26918discloses biphenylamidine derivatives having an anti blood-coagulationactivity.

As a method of synthesizing a compound having a biphenyl skeleton anduseful as an intermediate of the biphenylamidine derivative useful as anFX_(a) inhibitor, WO 99/26918 discloses a method comprising preparing3-cyanophenylboronic acid from 3-bromobenzonitrile and subjecting the3-cyanophenylboronic acid to a coupling reaction with3-iodo-3-(hydroxymethyl)benzoic acid compound, to provide a5-(3-cyanophenyl)-3-hydroxymethylbenzoic acid compound. This method,however is industrially disadvantageous in that the synthesis of3-cyanophenylboronic acid needs a reaction at an extremely lowtemperature of −78° C., and this extremely low temperature reaction isdifficult to effect in industrial practice, that the coupling reactionneeds to employ an iodine compound which is expensive, and that theresultant target compound must be purified by using a columnchromatography which is difficult to use in industrial practice.Further, each reaction step of the above-mentioned method has problemswhich are difficult to solve.

As a synthesis method of a phenylboronic acid compound, a method inwhich a halogenated benzene derivative is converted to an organic metalcompound of the derivative and then the organic metal compound reactswith a trialkyl borate, is known from, for example, “The Chemistry ofBoron”, Academic, N.Y., 1961; “Methods of Elemento-Organic Chemistry,North-Holland, Amsterdam, 1976, Vol. 1; “Organoborane Chemistry”,Academic, N.Y., 1975, etc.

In the above-mentioned method using the organic metal compound in thecase where the organic metal compound is a lithium compound, thereaction of the lithium compound with the trialkyl borate must beconducted at an extremely low temperature of −78° C. Also, in the casewhere the organic metal compound is a Grignard reagent and in the casewhere the halogenated benzene derivative has, as a substituent group, acyano group, it is difficult to prepare a boronic acid compound from theGrignard reagent.

Also, Japanese Unexamined Patent Publication No. 7-17937 discloses amethod of selectively reducing only one of two ester groups in anaromatic diester compound. However, this method is disadvantageous inthat when this method is utilized to synthesize5-bromo-3-hydroxymethylbenzoric acid derivative from a5-bromoisophthalic acid derivative, a side reaction by which both theester groups of the isophthalate diester are reduced to produce, as aby-product, 5-bromo-3-hydroxymethylbenzyl alcohol in a yield of about 10molar %, occurs. To remove the by-product, a product of any one of thesucceeding procedures must be subjected to a column chromatography whichis difficult to be conducted in industrial practice.

The coupling reaction of the boronic acid compound with a halogenatedaromatic compound is generally known as a SUZUKI coupling reaction.(Referential documents: Acvavces in Metal-Organic Chemistry, JAI PressInc, Vol. 6, page 187-243, Organic Lettes., Vol. 1, No. 7, page 965-967(1999), etc.). With respect to this coupling reaction, WO 00/69811discloses that the employment of tetrabutylammonium bromide causes thereaction to be completed within a short time. However, a new methodenabling the efficiency of the coupling reaction to be enhanced withoutusing the tetrabutylammonium bromide, is desired.

Various methods of oxidizing the aromatic compound having ahydroxymethyl group with manganese dioxide, which is cheap, in areaction medium comprising methylene chloride, to convert thehydroxymethyl group to a formyl group are known. (Referential documents:Polish J. Chem., 53, 1889 (1975) and Lectures of Experimental Chemistry,Vol. 23, page 21.) These conventional methods are disadvantageous inthat the employment of methylene chloride having a low boilingtemperature causes a recovery of methylene chloride to be difficult andmethylene chloride is harmful to the human body. Accordingly, it isdesired to develop a new method in which a reaction medium differentfrom methylene chloride and free from the above-mentioned disadvantagesis employed in place of methylene chloride.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a process for producinga 5-(3-cyanophenyl)-3-formylbenzoic acid compound, by a easy procedure,with a high yield and with a low cost.

The above-mentioned object can be obtained by the process of the presentinvention for producing a 5-(3-cyanophenyl)-3-formylbenzoic acidcompound.

The process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound comprises the steps of:

-   -   reacting a 5-bromo-(3-hydroxymethyl)benzoic acid compound        represented by the formula (I):        in which formula (I), R represents a hydrogen atom or a linear        or branched chain alkyl group having 1 to 10 carbon atoms, with        manganese dioxide, to prepare a 5-bromo-3-formylbenzoic acid        compound represented by the formula (II):        in which formula (II), R is as defined above; and    -   reacting the resultant 5-bromo-3-formylbenzoic acid compound        with 3-cyanophenylboronic acid represented by the formula (III):        in the presence of a palladium complex, to prepare a        5-(3-cyanophenyl)-3-formylbenzoic acid compound represented by        the formula (IV):        in which formula (IV), R is as defined above.

In the process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound, the3-cyanophenylboronic acid represented by the formula (III) is preferablyone prepared by reacting 3-formyl-phenylboronic acid represented by theformula (V):

with hydroxyamine hydrochloride.

In the process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound, the3-formylphenylboronic acid represented by the formula (V) is preferablyone prepared by reacting a 3-(dialkoxymethyl)bromobenzene represented bythe formula (VI):

in which formula (VI), R¹ represents a linear or branched chain alkylgroup having 1 to 4 carbon atoms, with magnesium metal to prepare anorganic magnesium compound of the 3-(dialkoxymethyl)bromobenzene; andthen further reacting the resultant organic magnesium compound with atrialkyl borate.

In the process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound, the5-bromo-3-(hydroxymethyl)benzoic acid compound represented by theformula (I) is preferably one prepared by reacting a 5-bromoisophthalicacid compound represented by the formula (VII):

in which formula (VII), R is as defined above, with sodium borohydride.

In the process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound, the5-bromo-3-(hydroxymethyl)benzoic acid compound prepared by the reactionof the 5-bromoisophthalic acid compound represented by the formula(VIII) with sodium borohydride, is preferably purified by using a mixedsolvent comprising an alcohol and a benzene derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

The process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound comprises:

(A) a step of reacting a 5-bromo-3-(hydroxymethyl)benzoic acid compoundrepresented by the formula (I):

in which formula (I), R represents a hydrogen atom or a linear orbranched chain alkyl group having 1 to 10 carbon atoms, with manganesedioxide, to prepare a 5-bromo-3-formylbenzoic acid compound representedby the formula (II):

in which formula (II), R is as defined above; and

(B) a step of reacting the resultant 5-bromo-3-formylbenzoic acidcompound with 3-cyanophenylboronic acid represented by the formula(III):

in the presence of a palladium complex, to prepare a5-(3-cyanophenyl)-3-formylbenzoic acid compound represented by theformula (IV):

in which formula (IV), R is as defined above.

In the above-mentioned step (A), the 5-bromo-3-(hydroxymethyl)benzoicacid compound of the formula (I) includes5-bromo-3-(hydroxymethyl)benzoic acid and C₁-C₁₀ linear or branchedalkyl esters of the acid. Namely, in the formula (I), R represents ahydrogen atom or a C₁-C₁₀ linear or branched alkyl group. The reactionof the 5-bromo-3-(hydroxymethyl)benzoic acid compound with manganesedioxide is preferably carried out in an organic solvent comprising atleast one member selected from, for example, toluene, xylene, ethylacetate, acetone, methylethylketone (MEK) and tetrahydrofuran (THF). Inthis reaction, the reaction temperature is preferably in the range offrom 30 to 180° C., more preferably, from 80 to 150° C. This reactionmay be carried out under the ambient atmospheric pressure, a reducedpressure or an increased pressure. Usually, the reaction is preferablyconducted under the ambient atmospheric pressure. Also, the reactiontime can be appropriately established in response to the reactiontemperature, usually is preferably in the range of from 0.5 to 10 hours.

In the step (A), manganese dioxide is preferably employed in a molaramount of 2 to 15 times, more preferably 4 to 8 times, that of the5-bromo-3-(hydroxymethyl)benzoic acid compound. If the manganese dioxideis employed in a molar amount of less than 2 times that of the benzoicacid compound, the reaction may not be completed within a practicallyapplicable reaction time, and thus portions of the starting compoundsmay remain unreacted. Also, if manganese dioxide is used in a molaramount of more than 15 times the benzoic acid compound, additionalby-products may be generated.

In the reaction step (A) of the process of the present invention, thehydroxymethyl group of the 5-bromo-3-(hydroxymethyl)benzoic acidcompound of the formula (I) is oxidized with manganese dioxide andconverted to a formyl group, to prepare a 5-bromo-3-formylbenzoic acidcompound. After the reaction is completed, the reaction mixture liquidis cooled to room temperature and filtered.

The resultant filtrate liquid is concentrated to obtain5-bromo-3-formylbenzoic acid compound.

In the reaction step (B) of the process of the present invention, the5-bromo-3-formylbenzoic acid compound of the formula (II) prepared inthe step (A) is reacted with 3-cyanophenylboronic acid of the formula(III) in the presence of a palladium complex (a catalyst) to prepare thetarget compound, namely a 5-(3-cyanophenyl)-3-formylbenzoic acidcompound of the general formula (IV). The palladium complex ispreferably selected from, for example, zero-valence palladium complexes,for example, tetrakistriphenylphosphine palladium and divalencepalladium complexes, for example, palladium diacetate, palladiumdichloride and bistriphenylphosphine palladium dichloride, and palladiumdiacetate is more preferably employed for the present invention. Thepalladium complex is preferably employed in a molar amount of 0.001 to50 molar %, more preferably 0.1 to 5 molar %, on the basis of the molaramount of the 5-bromo-3-formylbenzoic acid compound used in the reactionstep (B). If the amount of the palladium catalyst present in thereaction of the step (B) is less than 0.001 molar % on the basis of themolar amount of the 5-bromo-3-formylbenzoic acid compound, the reactiontime necessary to complete the reaction may become too long, and if theamount of the palladium catalyst is more than 50 molar %, the resultanttarget compound may be difficult to purify. The reaction mixture for thereaction step (B) preferably contain a basic compound as a neutralizingagent. For the basic compound, at least one member selected from sodiumhydrogen carbonate, potassium hydrogen carbonate, potassium carbonateand potassium phosphate hydride is preferably employed. Among thesecompounds, sodium hydrogen carbonate and/or potassium hydrogen carbonateis preferably employed. The basic compound is preferably employed in amolar amount of 2 to 5 times, more preferably 2 to 4 times, the molaramount of the 3-cyanophenylboronic acid. The reaction solvent for thereaction step (B) preferably comprises at least one member selected fromwater-containing dimethylformamide, water-containing dimethylacetamide,water-containing N-methylpyrrolidone, water-containingN,N-dimethylimidazolidinone and water-containing THF. Particularly, thewater-containing dimethylformamide is more preferably employed.

The reaction of the step (B) is preferably conducted in a non-reactivegaseous atmosphere, for example, an atmosphere of an inert gas, forexample, an argon gas atmosphere or nitrogen gas atmosphere. Thereaction temperature of the step (B) is preferably 30 to 150° C., morepreferably 50 to 100° C. Also, the reaction pressure of the step (B) maybe any one of the ambient atmospheric pressure, reduced pressures andincreased pressures, and usually, the ambient atmospheric pressure ispreferably applied to the reaction of the step (B). The reaction timefor the step (B) is appropriately established in response to thereaction temperature and usually is preferably in the range of from 0.1to 24 hours, more preferably from 0.5 to 10 hours.

After the reaction of the step (B) is completed, the resultant reactionmixture liquid is filtered under hot conditions, the resultant filtrateliquid is heated to a temperature of 50 to 100° C., water is added tothe heated reaction mixture liquid, the resultant precipitates arecollected by, for example, filtration, to obtain the target compound.

Optionally, the collected precipitate is heat-dissolved in awater-containing tetrahydrofuran (THF) at a temperature of 50 to 100° C.and the resultant solution is mixed with an alkyl alcohol having 1 to 3carbon atoms to recrystallize and purify the target compound.

The water-containing THF preferably has a water content of 0.5 to 10% bymass, more preferably 1 to 5% by mass. The water-containing THF ispreferably employed in an amount by mass of 1 to 6 times the mass of thecollected precipitate. The alkyl alcohol is preferably selected frommethyl alcohol, ethyl alcohol, 2-propyl alcohol and 1-propyl alcohol.Particularly, 2-propyl alcohol is preferably employed to purify thetarget compound. The alkyl alcohol is preferably employed in an amountby mass of 1 to 10 times the mass of the water-containing THF.

The 5-bromo-3-(hydroxymethyl)benzoic acid compound of the generalformula (I) usable for the reaction step (A) of the process of thepresent invention may be produced by a conventional production process.The compound is preferably one produced by a reaction of a5-bromoisophthalic acid compound represented by the general formula(VII) with sodium borohydride (NaBH₄). Preferably, sodium borohydridefor the above-mentioned reaction is employed in a molar amount of 0.5 to2 times, more preferably 0.8 to 1.4 times, the molar amount of the5-bromo-isophthalic acid compound of the formula (VII). If the molaramount of sodium borohydride is less than 0.5 time the molar amount ofthe compound of the formula (VII), the reaction may not completed withina practical reaction time, and if the molar amount of NaBH4 is more than2 times that of the compound of the formula (VII), the generation ofby-products may occur in too large a yield. The reaction pressure may bethe ambient atmospheric pressure, a reduced pressure or an increasedpressure. Usually, the reaction is preferably carried out under theambient atmospheric pressure. The reaction procedure is preferablycarried out in a reaction solvent comprising at least one memberselected from, for example, tetrahydrofuran, diethyl ether and dioxane.

The resultant 5-bromo-3-(hydroxymethyl)benzoic acid compound from theabove-mentioned reaction can be isolated from the reaction mixtureliquid by, for example, an extraction procedure. The extracting mediummay comprise an acetate ester solvents, for example, ethyl acetate,methyl acetate or isopropyl acetate; aromatic solvents, for example,toluene and xylene; ether solvents, for example, THF and diethylether;and ketone solvents, for example, methylethylhetone.

The crude product of 5-bromo-3-(hydroxymethyl)benzoic acid compoundisolated from the reaction mixture liquid by the above-mentionedprocedure contains, as a reaction by-product,5-bromo-3-(hydroxymethyl)benzyl alcohol. To purify the5-bromo-3-(hydroxymethyl)benzoic acid compound by separation removingthe by-product, the crude product of the5-bromo-3-(hydroxymethyl)benzoic acid compound is further purified byusing a mixed solvent comprising an alcohol and a benzene derivative.The above-mentioned alcohol include methyl alcohol, ethyl alcohol and/orethylene glycol. Among then, methyl alcohol, which has a high solubilityin water and in benzene derivatives and a high dissolving property tothe by-product, is preferably employed. The benzene derivatives for themixed solvent preferably comprises an alkylated benzene compound, forexample, xylene, or toluene. More preferably, xylene having a highdissolving property for alcohols is employed.

In the above-mentioned purifying procedure, the crude product of the5-bromo-3-(hydroxymethyl)benzoic acid compound is dissolved in analcohol, for example, methyl alcohol, the solution is mixed with water,the resultant mixture liquid is mixed with a benzene derivative, forexample, toluene or xylene, to extract the5-bromo-3-(hydroxymethyl)benzoic acid compound in an organic phasefraction of the mixture liquid. The resultant extract liquid is washed,dried and concentrated to collect the purified5-bromo-3-(hydroxymethyl)benzoic acid compound.

3-cyanophenylboronic acid of the formula (III) usable for the step (B)of the process of the present invention may be produced by anappropriate method. Preferably, 3-cyanophenylboronic acid is produced byreacting 3-formylphenylboronic acid of the formula (V) withhydroxylamine hydrochloride. In this production method, the reaction of3-formylphenylboronic acid with hydroxylamine hydrochloride ispreferably conducted in an organic solvent comprising at least onemember selected from formic acid, acetic acid and propionic acid, morepreferably in formic acid. The organic solvent is preferably used in anamount by mass of 5 to 15 times the amount by mass of the3-formylphenylboronic acid subjected to the reaction. Also, thisreaction is carried out at a reaction temperature of 90° C. to theheat-refluxing temperature of the reaction for a reaction time of 0.5 to24 hours, more preferably 5 to 8 hours. After the completion of thereaction, the target compound, for example, 3-cyanophenylboronic acid ofthe formula (III), can be collected from the resultant reaction mixtureby recrystallizing the target compound. The above-mentioned productionmethod of 3-cyanophenylboronic acid does not need to be carried out atan extremely low temperature and can be effected by a simple reactionprocedure, and thus the resultant 3-cyanophenylboronic acid from thismethod is advantageous in a high degree of purity thereof.

3-formylphenylboronic acid of the formula (V) usable as a startingmaterial for the production reaction of the above-mentioned3-cyanophenylboronic acid may be produced by an appropriate method.Particularly, it is preferable that 3-formylphenylboronic acid be oneproduced by reacting 3-(dialkoxymethyl)bromobenzene, in which the alkylgroup in the alkoxyl group in the alkoxymethyl group is preferablyselected from C₁-C₄ linear and branched alkyl groups, more preferablymethyl and ethyl groups, with metallic magnesium to prepare an organicmagnesium compound thereof, and then reacting the organic magnesiumcompound with a trialkyl borate compound. The reaction for thepreparation of the above-mentioned organic magnesium compound is carriedout in an organic solvent which is not limited to a specific type ofsolvent as long as the solvent can dissolve therein3-(dialkoxymethyl)bromobenzene, and is inert to the reaction of the3-(dialkoxymethyl)bromobenzene with the magnesium metal. Usually, theorganic solvent preferably comprises an ether selected from, forexample, diethylether, tetrahydrofuran, tert-butylmethylether, anddiisopropylether or a mixture of the above-mentioned ether compounds,more preferably diethylether, tetrahydrofuran, tert-butylmethylether ora mixture thereof. The metallic magnesium is preferably used, for thereaction, in a molar amount of 0.6 to 3 times the molar amount of the3-(dialkoxymethyl)bromobenzene.

If the metallic magnesium is used in a molar amount of less than 0.6times, the target compound may be obtained in an unsatisfactory yield,and if the magnesium metal is used in a molar amount of more than 3times, undesired by-products may be produced and the resultant reactionmixture may be difficult to after-treato. The reaction with themagnesium metal in preferably carried out at a temperature of 0 to 100°C. for a time of 0.5 to 24 hours, more preferably at 10 to 80° C. for0.5 to 10 hours. This reaction may be carried out under any pressurecondition, for example, the ambient atmospheric pressure, a reducedpressure or an increased pressure. Usually, the reaction is preferablycarried out under the ambient atmospheric pressure.

The resultant organic magnesium compound from the above-mentionedreaction is subjected to a reaction with a trialkyl borate. The trialkylborate usable for the reaction is preferably selected from, for example,trimethyl borate, triethyl borate, triisopropyl borate and tri-n-butylborate, more preferably trimethyl borate.

The reaction of the organic magnesium compound with a trialkyl boratecompound is preferably carried out at a reaction temperature of −70° C.to +20° C. for a reaction time of 0.5 to 24 hours, more preferably at−10 to +20° C. for 0.5 to 12 hours.

The above-mentioned process for producing 3-formylphenylboronic acidcompound is advantageous in that no low temperature reaction isnecessary, and the resultant 3-formylphenylboronic acid compound isadvantageous in that the degree of purity thereof is high.

EXAMPLE

The present invention will be further explained by the followingexamples which are not intended to limit the scope of the presentinvention in any way.

Production Example 1

Preparation and Purification of methyl 5-bromo-3-(hydroxymethyl)benzoate(the Formula (I))

A three-necked flask having a capacity of 2 liters was charged with109.2 g of dimethyl 5-bromo-isophthalate and then with 400 ml oftetrahydrofuran (THF), to prepare a solution of dimethyl5-bromoisophthalate. The solution was mixed with 16.6 g of sodiumborohydride and the resultant mixture liquid was agitated while coolingthe mixture liquid with ice pieces. Separately, 40.5 ml of methylalcohol were dissolved in 150 ml of THF, the resultant solution wasmixed in the ice-cooled mixture liquid. Then, the resultant reactionmixture liquid was agitated for 5 hours while cooling with ice pieces.The reaction mixture liquid was added with 380 ml of water to terminatethe reaction, and then mixed with a 1 mole hydrochloric acid solution toadjust the pH value of the reaction mixture liquid to 7.0. The resultantreaction mixture liquid was subjected to an extraction treatment with380 ml of ethyl acetate and then with 200 ml of ethyl acetate. Theresultant organic extract liquids were mixed with each other, and theresultant mixed extract liquid was washed with 300 ml of water and thenwith 80 ml of a saturated aqueous common salt solution, and theresultant washed extract liquid was dried with a drying agent consistingof anhydrous magnesium sulfate.

The dried extract liquid was filtered to separate the drying agent, andthe resultant filtrate was concentrated. A crude product of the targetcompound, namely methyl 5-bromo-3-(hydroxymethyl)benzoate was obtainedin an amount of 96.5 g. In the crude product, the mass ratio of thetarget compound, namely methyl 5-bromo-3-(hydroxymethyl)benzoate to theby-product consisting of 5-bromo-3-(hydroxymethyl)benzyl alcohol was88:10, as determined by NMR measurement.

The crude product was dissolved in 160 ml of methyl alcohol; theresultant solution was placed in a separatory funnel and mixed with 160ml of water and 1000 ml of xylene; and the resultant mixture liquid wassubjected to a phase separation. The resultant organic phase fractionwas collected, washed with 160 ml of a solution of methyl alcohol inwater in volume ratio of 1:1, then with 160 ml of water and finally with160 ml of a saturated aqueous common salt solution. The washed organicphase fraction was dried with a drying agent consisting of anhydrousmagnesium sulfate. The dried solution was subjected to a filtrationprocedure to remove the drying agent from the organic phase fraction.Then, the filtrate was concentrated. The target compound, namely,purified methyl 5-bromo-3-(hydroxymethyl)benzoate was obtained in anamount of 81.98 g. The yield thereof was 83.3%. In the resultantpurified product, a mass ratio of the target compound, methyl5-bromo-3-(hydroxymethyl)benzoate to a by-product, namely,5-bromo-3-(hydroxymethyl)benzyl alcohol was 96:1.8, determined by theNMR measurement. The results of the ¹H-NMR measurement (200 MHz, δ ppm,CDCl₃) were as follows

3.93(s, 3H), 4.74 (d, J=5.6 Hz, 2H)

7.73 (s, 1H), 7.95 (s, 1H), 8.09 (s, 1H).

Production Example 2

Preparation of 3-formylphenylboronic acid (the Formula (VI)

A three-necked flask with a capacity of 2 liters was charged with 24.9 gof metallic magnesium. Separately, a solution was prepared by dissolving215.34 g of 3-(dimethoxymethyl)bromobenzene in 1095 ml of THF.

The three-necked flask containing the magnesium metal was furthercharged with the THF solution in an amount of 75 ml and then with 1.07ml of a reaction initiator consisting of 1,2-dibromoethane. When anexothermic reaction is initiated in the reaction mixture in thethree-necked flask, the remaining amount of the THF solution wasgradually dropped into the flask to such an extent that the reactionmixture is moderately refluxed. After the dropping procedure of the THFsolution was completed, the resultant reaction mixture liquid in theflask was agitated at room temperature for one hour. A Grignard reagentconsisting of a magnesium compound of 3-(dimethoxymethyl)bromobenzenewas obtained.

Separately, a three-necked flask having a capacity of 3 liters wascharged with 154.8 ml of trimethyl borate and then with 915 ml of THF toprepare a solution of trimethyl borate in THF. The solution was agitatedwhile a nitrogen gas flowed through the flask and the solution wascooled with ice. The ice-cooled THF solution was mixed with the Grignardreagent fed into the 3 liter flask through a stainless steel pipe.

The resultant reaction mixture liquid was agitated for one hour whilecooling with ice, and then further mixed with an aqueous sulfuric acidsolution prepared from 30 ml of concentrated sulfuric acid and 480 ml ofwater. The temperature of the resultant admixture liquid was raised toroom temperature and, then, the admixture liquid was agitated at thistemperature for 2 hours. Thereafter, the agitation was stopped and theresultant reaction mixture liquid was left to stand in the ambientatmosphere for one night.

The precipitate generated in the reaction mixture liquid was removed byfiltration and the resultant filtrate was concentrated. The resultantconcentration residue was mixed with water in a volume equal to that ofthe concentration residue, the resultant mixture liquid was agitated atroom temperature for one hour. The resultant solid fraction wascollected from the mixture liquid by filtration and dried. The targetcompound 3-formylphenylboronic acid was obtained in an amount of 123.46g. The yield thereof was 88%. The results of the ¹H-NMR measurement ofthe resultant target compound (200 MHz, δ ppm, CDCl₃) were as follows.

7.54 (t, J=7.5 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H),

7.9-8.1 (br. d, 1H), 8.2-8.3 (br. s, 1H), 10.04 (s, 1H)

Production Example 3

Preparation of 3-cyanophenylboronic acid (of the Formula (III))

In a three-necked flask with a capacity 3 liters, 123.4 g of the3-formylphenylboronic acid prepared in Production Example 2, 68.6 g ofhydroxylamine hydrochloride, 1050 ml of formic acid and 112.1 g ofsodium formate are placed and mixed with each other. The resultantmixture liquid was heated for 8 hours while refluxing. The resultantreaction mixture liquid was left to stand in the ambient atmosphere forone night. Thereafter, in the case where a precipitate was generated inthe reaction mixture liquid, this mixture liquid was agitated whilecooling with ice and, in the case where no precipitate was generated inthe reaction mixture liquid, the mixture liquid was mixed with a smallamount of precipitation seed particles and agitated. From the resultantreaction mixture liquid, the solid precipitate was collected, byfiltration and dried. The target compound, 3-cyanophenylboronic acid wasobtained in an amount of 82.0 g. The yield thereof was 68%. The resultsof the ¹H-NMR measurement of the target compound (200 MHz, δ ppm, CDCl₃)were shown below.

7.47 (t, J=7.7 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H),

7.9-8.0 (br. d, 1H), 8.0-8.1 (br. s, 1H)

EXAMPLE

Preparation of methyl 5-(3-cyanophenyl)-3-formylbenzoate

Step (A) Preparation of methyl 5-bromo-3-formylbenzoate

In a three-necked flask with a capacity of 3 liters, 253.11 g of methyl5-bromo-3-(hydroxymethyl)benzoate were placed and mixed with 2000 ml oftoluene, and the resultant mixture was agitated to prepare a solution.The resultant solution was mixed with 44 g of manganese dioxide, and theresultant reaction mixture liquid was heated to a temperature of 105° C.and agitated for 7 hours. The resultant reaction mixture liquid wasallowed to be cooled to room temperature and filtered to remove a solidfraction therefrom, and the resultant filtrate was concentrated. Thetarget compound, methyl 5-bromo-3-formylbenzoate was obtained in anamount of 236.79 g which corresponded to a yield of 94.3%.

The results of the ¹H-NMR (200 MHz, δ ppm, CDCl₃) of the resultantcompound were as follows.

3.98 (s, 3H), 8.1-8.3 (m, 1H),

8.3-8.6 (m, 2H), 10.0 (s, 1H)

Step (B) Preparation of methyl 5-(3-cyanophenyl)-3-formylbenzoate

In a three-necked flask with a capacity of 2 liters,3-cyanophenylboronic acid in an amount of 67.65 g and sodium hydrogencarbonate in an amount of 116.0 g were placed and then a solution of111.9 g of methyl 5-bromo-3-formylbenzoate prepared in step (A) in 142ml of dimethyl formamide (DMF) was placed. The resultant mixture liquidin the flask was mixed with 592 ml of DMF and 149 ml of water. The flaskwas gas-tightly sealed, the air inside the flask was replaced by anargon gas and then 0.2231 g of palladium acetate was fed into the flask.The resultant reaction mixture liquid in the flask was heated to atemperature of 80° C. and agitated at this temperature for 6.5 hours.

Thereafter, the resultant reaction mixture liquid was subjected to ahot-filtration to remove an insoluble fraction from the reaction mixtureliquid, and the resultant filtrate was heated to a temperatures of 80°C. and agitated. The heated and agitated filtrate was gradually addedwith 585 ml of water, and the resultant filtrate mixture was left tocool to room temperature. The precipitate generated in the filtratemixture was collected by filtration, and the collected precipitate waswashed with 590 ml of water and then dried. A crude product of thetarget compound, methyl 5-(3-cyanophenyl)-3-formylbenzoate was obtainedin an amount of 103.15 g which corresponded to a yield of 84.5%.

The crude product was subjected to a purification procedure as follows.

The dried crude product in an amount of 50 g was placed in athree-necked flask with a capacity of 2 liters and mixed with 150 ml ofhydrous THF having a water content of 3%. The resultant mixture washeated to a temperature of 80° C. to provide a solution of the crudeproduct. The solution was subjected to a hot-filtration. The filtratewas again heated to a temperature of 80° C. and mixed with 750 ml of2-propyl alcohol. The resultant mixture liquid was left to cool to roomtemperature, to recrystallize the target compound. After cooling, theresultant precipitate generated in the cooled mixture liquid wascollected by filtration. A purified product of the target compound,methyl 5-(3-cyanophenyl)-3-formylbenzoate was obtained in an amount of45.19 g which corresponded to a recrystallization yield of 90%. Theresult of the ¹H-NMR (200 MHz, δ ppm, CDCl₃) of the purified product wasas follows.

4.02 (s, 3H), 7.5-7.8 (m, 2H),

7.8-8.0 (m, 2H), 8.2-8.3 (s, 1H),

8.4-8.6 (m, 2H), 10.2 (s, 1H)

INDUSTRIAL APPLICABILITY OF THE INVENTION

The process of the present invention for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound enables a5-(3-cyanophenyl)-3-formylbenzoic acid compound useful as anintermediate of medicines, particularly, inhibitors against selectiveactivated blood coagulation factor X (FX_(a)), to be produced by easyprocedures applicable to industrial practice and containing no columnchromatography step, with a high yield and with a low cost, andtherefore has a high applicability to industrial practice.

1. A process for producing a 5-(3-cyanophenyl)-3-formylbenzoic acidcompound comprising the steps of: reacting a5-bromo-(3-hydroxymethyl)benzoic acid compound represented by theformula (I):

in which formula (I), R represents a hydrogen atom or a linear orbranched chain alkyl group having 1 to 10 carbon atoms, with manganesedioxide, to prepare a 5-bromo-3-formylbenzoic acid compound representedby the formula (II):

in which formula (II), R is as defined above; and reacting the resultant5-bromo-3-formylbenzoic acid compound with 3-cyanophenylboronic acidrepresented by the formula (III):

in the presence of a palladium complex, to prepare a5-(3-cyanophenyl)-3-formylbenzoic acid compound represented by theformula (IV):

in which formula (IV), R is as defined above.
 2. The process forproducing a 5-(3-cyanophenyl)-3-formylbenzoic acid compound as claimedin claim 1, wherein the 3-cyanophenylboronic acid represented by theformula (III) is one prepared by reacting 3-formyl-phenylboronic acidrepresented by the formula (V):

with hydroxyamine hydrochloride.
 3. The process for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound as claimed in claim 2,wherein the 3-formylphenylboronic acid represented by the formula (V) isone prepared by reacting a 3-(dialkoxymethyl)bromobenzene represented bythe formula (VI):

in which formula (VI), R¹ represents a linear or branched chain alkylgroup having 1 to 4 carbon atoms, with magnesium metal to prepare anorganic magnesium compound of the 3-(dialkoxymethyl)bromobenzene; andthen further reacting the resultant organic magnesium compound with atrialkyl borate.
 4. The process for producing a5-(3-cyanophenyl)-3-formylbenzoic acid compound as claimed in claim 1,wherein the 5-bromo-3-(hydroxymethyl)benzoic acid compound representedby the formula (I) is one prepared by reacting a 5-bromoisophthalic acidcompound represented by the formula (VII):

in which formula (VII), R is as defined above, with sodium borohydride.5. The process for producing a 5-(3-cyanophenyl)-3-formylbenzoic acidcompound as claimed in claim 4, wherein the5-bromo-3-(hydroxymethyl)benzoic acid compound prepared by the reactionof the 5-bromoisophthalic acid compound represented by the formula (VII)with sodium borohydride, is purified by using a mixed solvent comprisingan alcohol and a benzene derivative.